# Investigating the contribution of paternal nucleosomes using the Gcn5 knock-out mouse

> **NIH NIH R03** · UNIVERSITY OF PENNSYLVANIA · 2022 · $1

## Abstract

ABSTRACT
 Infertility affects approximately 15% of couples in the United States, with males contributing in nearly
50% of these cases. One potential mechanism underlying infertility are alterations to the paternal epigenome.
Mammalian spermatozoa exhibit a unique, highly compacted and condensed DNA structure that is strongly
dependent on epigenetic mechanisms, including histone hyperacetylation followed by nucleosome eviction.
Specifically, 90-99% of sperm nucleosomes are evicted and replaced with protamines, allowing for this
remarkable degree of compaction. Human sperm exhibiting altered ratios of protamines or excess histone
retention are associated with infertility and altered embryogenesis following IVF/ICSI. However, the exact
cause of altered embryogenesis as a result of abnormal nucleosome retention, and ultimately, potential
regulatory functions and mechanisms by which paternally contributed histones affect early development,
remain largely unknown. We have previously developed a conditional mouse mutant where the histone
acetyltransferase Gcn5 is ablated in pre-meiotic germ cells (Gcn5cKO). One relevant feature of this model is
that mature sperm have increased histone retention and decreased fertility. This model provides the ability to
study the effect of paternal nucleosome contributions to the embryo, and determine the consequences of
abnormal paternal nucleosome contribution on embryonic development. We propose that the paternal
epigenome, specifically nucleosomes, play a role in regulating early embryonic chromatin and
transcriptional dynamics, thus leading to proper embryonic development.
 We will utilize our Gcn5cKO mouse model to introduce an abnormal complement of sperm nucleosomes
into embryos and investigate the following Specific Aims: (1) To determine if excess paternal nucleosomes
alter the kinetics and successful development of pre-implantation embryos and (2) determine if abnormally
retained paternal nucleosomes alter chromatin dynamics and transcription in pre-implantation embryos.
Together, the proposed research will provide important insight into the mechanisms governing early embryonic
development, including the effects of the paternal epigenome on chromatin dynamics and zygotic genome
activation. It will additionally provide evidence as to why abnormal paternal chromatin results in infertility and
altered embryogenesis in humans. The results of these studies have the potential to ultimately impact clinical
management of patients diagnosed with infertility.

## Key facts

- **NIH application ID:** 10491990
- **Project number:** 5R03HD104104-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Lacey J Luense
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1
- **Award type:** 5
- **Project period:** 2021-09-21 → 2022-09-02

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10491990

## Citation

> US National Institutes of Health, RePORTER application 10491990, Investigating the contribution of paternal nucleosomes using the Gcn5 knock-out mouse (5R03HD104104-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10491990. Licensed CC0.

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